The invention relates to novel pharmaceutical release systems for basic drugs with pH-dependent water solubility such as flibanserin. Flibanserin is a known benzimidazolon derivative having the summation formula C20H21F3N4O represented by the chemical indication 1,3-dihydro-1-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]-2H-benzimidazole-2-one which was already disclosed in 1992 in form of its hydrochloride in EP-A-526 434 and has the following chemical formula:

Flibanserin is a known post-synaptic full serotonin (5-HT1A) agonist and 5-HT2A antagonist. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, and anxiety. Immediate release tablets containing flibanserin (e.g. as described in WO 03/097058) are well tolerated, but patient compliance would be much improved if a once-daily regimen were possible and if side effects could further be reduced. Such a pharmaceutical release system of flibanserin would have not only the advantage of a higher patient compliance but would also be advantageous in having a reduced potential to cause undesirable side effects by reducing the average maximum flibanserin plasma concentration Cmax.
In acidic environment compounds such as flibanserin are usually very well water soluble whereas in neutral or basic environment these drugs can be practically insoluble. For example, flibanserin shows a solubility of 6.2 mg/ml in 0.1 N HCl and a solubility of 0.002 mg/ml in 0.05 M phosphate buffer pH 6.8. These physicochemical properties of basic compounds make it difficult to develop extended release dosage forms. There is a natural pH gradient from the acidity of the stomach where the pH of physiological fluids are typically around 1-2, through the weakly acidic duodenum to the virtually neutral environment of the small intestine where the pH is in the range of 5-8.
The drug release of flibanserin from conventional systems containing only pH-independent swelling polymers would be much faster in the stomach compared to the slower or even incomplete drug release in the small intestine and the colon. Formulations containing only pH-dependent retarding polymers would not allow for drug release over an extended period of time because these polymers loose their retarding effect above a certain pH. For example, Eudragit® L 100-55 forms an insoluble and impermeable film below pH 5.5, but dissolves above this pH, Carbomers form an insoluble barrier in the stomach but a more permeable gel layer in the intestine and alginic acids form an insoluble gel layer in acidic environment, but are converted to the soluble sodium alginates at a higher pH. As a result it is also difficult to find out functional excipients which would provide an improved bioavailability over the whole gastrointestinal tract for basic drugs with pH-dependent water solubility.
In prior art a number of approaches are described which provide release systems:
For example U.S. Pat. No. 4,792,452 describes a controlled release pharmaceutical formulation from which a pharmaceutical of a basic character is released at a controlled rate irrespective of the pH of the environment, consisting essentially of a pharmaceutical of a basic character, a pH-dependent polymer which is a salt of alginic acid, in an amount of from about 15 to about 45% by weight of the formulation, said salt of alginic acid having a viscosity of within the range from about 4 to about 500 centipoises in 1% solution at 25° C.; a pH-independent hydrocolloid gelling agent having a viscosity within the range of from about 50 to about 100,000 centipoises in 2% solution at 20° C., in an amount within the range of from about 3 to about 35% by weight of the formulation, and binder, whereby said formulation being free of calcium ion. The drug used is preferably a calcium channel blocker such as verapamil usually formulated in form of its hydrochloride.
As already explained after oral administration the alginates present in the controlled release pharmaceutical formulation are converted to alginic acid in the stomach and form an insoluble gel layer around the tablet particularly in the presence of calcium ions. Therefore, calcium ions are expressly excluded, which provides a very limited usability of the proposed formulation.
Furthermore, U.S. Pat. No. 4,968,508 is directed to a sustained release matrix formulation in tablet unit dosage form comprising from about 0.1% by weight to about 90% by weight of cefaclor, from about 5% by weight to about 29% by weight of a hydrophilic polymer, and from about 0.5% by weight to about 25% by weight of an acrylic polymer which dissolves at a pH in the range of about 5.0 to about 7.4, with the proviso that the total weight of the hydrophilic polymer and said acrylic polymer is less than 30% by weight of the formulation. The active substance is an antimicrobial agent, namely cefaclor, i.e. the proposed formulation is especially designed for zwitterions having both an acidic and a basic functional group having very specific requirements.
It is therefore an object of the present invention to provide improved pharmaceutical release systems which avoid the disadvantages of the prior art, and allow to provide a pH-independent release profile in order to improve the bioavailability of flibanserin and which exhibit the desirable pharmacokinetic profiles (e.g. by allowing once-daily dosing regimen and/or reducing side effects). Furthermore a method of manufacturing the same shall be provided.